The compounds of α,β-unsaturated aryl sulfones are small molecule kinase regulatory compounds that have been developed for modifying cell cycle distribution patterns in cancer cells subjected to radiation therapy, and they have been identified as a potential candidate for radiation protection studies. These compounds are described in U.S. Pat. Nos. 6,656,973 and 6,667,346, which are particularly incorporated herein by reference in their entirety.
Certain compounds of α,β-unsaturated aryl sulfones and specific formulations regarding suspension and/or aqueous compositions of these compounds have also been previously described in the PCT Application WO 2007/016201 and the PCT Application WO 2008/105808, contents of which are particularly incorporated herein by reference in their entireties
The α,β-unsaturated aryl sulfones, in particular α,β unsaturated benzyl styryl sulfones, have demonstrated significant and selective systemic protection of normal cells from radiation-induced damage in animals. It has also been demonstrated that compounds of α,β-unsaturated aryl sulfones exhibit protection of DNA, bone marrow, stem cells, gastrointestinal crypt cells, and amelioration of cytopenia from radiation. These classes of compounds have also shown to possess antiproliferative activity and selectivity in the killing of proliferating cells such as tumor cells, but not normal cells.
Radiation protection provided by compounds of α,β-unsaturated aryl sulfone is achieved through regulation levels of pro-apoptosis proteins such as p53 as well as its downstream regulators p21, Bax, c-Abl and p73, indicating that these compounds could rescue cells from ionizing radiation-induced p53-dependent apoptosis. Sanchita P. Ghosh et al, Radiation Protection by a New Chemical Entity, Ex-Rad: Efficacy and Mechanisms, Radiation Research 171,000-000 (2009).
While apoptosis has been previously described for many physiological processes, one area that has only recently been under investigation is skin wound healing. Apoptosis is vital to normal wound healing, especially in the removal of inflammatory cells and scar formation. As cell populations rapidly proliferate during tissue reconstruction, cell growth is balanced by apoptosis. Inflammatory cells, for example, must be removed in order to begin the next stage of wound healing. Otherwise, persistent inflammation can lead to non healing wounds. Similarly, the granulation tissue must decrease in cellularity to evolve into a scar. Recent research has elucidated some of the key roles of apoptosis in the wound healing process.
The role of pro-apoptosis protein P21 in modulation and repair of wounds has previously been demonstrated by Michelle Olive et al. “p21 modulats arterial wound repair” in J Clin Invest.; 118(6): 2050-2061 2008. It has been demonstrated that that p21 is a key mediator of vascular proliferation in response to injury and that p21 modulates arterial wound repair and its activity is essential for the regulation of cell proliferation and inflammation after arterial injury in local vascular cells.
U.S. Pat. No. 6,486,210 discloses compounds of α,β-unsaturated aryl sulfone having demonstrated apoptosis and anticancer chemotherapeutic activities through binding to target receptor tyrosine kinases such as Mitogen Activated Protein Kinase (MAPK) that result in regulating the kinase cascade (e.g., Ras/Raf/MEK/ERK kinase cascade). The best understood MAPK pathway involves extracellular signal-regulated kinases which constitute the Ras/Raf/MEK/ERK kinase cascade (Boudewijn et al., Trends Biochem. Sci. 20, 18 (1995)). Once this pathway is activated by different stimuli, MAPK phosphorylates a variety of proteins including several transcription factors which translocate into the nucleus and activate gene transcription. Negative regulation of this pathway could arrest the cascade of these events.
It has been shown that MAPK has a critical role in the proliferation and control of hematopoietic progenitor cells. Masayuki Towatari et al. The Journal of Biological Chemistry, 270, 4101-4107 (1995.) It has also been shown that MAPK is involved in activation of osteogenic differentiation of adult stem cells and suggest that commitment of cells into osteogenic or adipogenic lineages is governed by activation or inhibition of family members of mitogen activatedprotein kinase. Rama K. Jaiswal et al, The American Society for Biochemistry and Molecular Biology, Inc. Vol. 275, No. 13, pp. 9645-9652 (2000).
Stem cells including hematopoietic stem cells have very important roles in a number of different processes in the body. For example, leukocytic hematopoietic cells are important in maintaining the body's defenses against disease; monocytes, macrophages and lymphocytes are involved in potentiating the body's responses to infection and tumors, while granulocytes are involved in overcoming infection, parasites and tumors. Platelets, another hematopoietic cell, form an important element in the hemostatic mechanism through initiating thrombus formation by their adhesion to each other and to damaged surfaces, and by the release of factors which assist in the formation of the fibrin clot. Erythrocytes are mainly involved in the transport of oxygen.
Recruitment of stem cells and/or progenitor cells is important in a variety of applications related to inflammation and wound healing. Vasculogenesis, which involves the growth of vessels derived from endothelial progenitor cells, is an example of such a process. Vasculogenesis, as well as angiogenesis, the process by which new blood vessels are formed from extant capillaries, and the factors that regulate these processes, are important in inflammation, and wound healing, and also contribute to pathologic conditions such as tumor growth, diabetic retinopathy, rheumatoid arthritis, and chronic inflammatory diseases (see, e.g., U.S. Pat. No. 5,318,957; Yancopoulos et al. Cell 93:661-4 (1998); Folkman et al. Cell 87; 1153-5 (1996); and Hanahan et al. Cell 86:353-64 (1996)).
Both angiogenesis and vasculogenesis involve the proliferation of endothelial cells. Endothelial cells line the walls of blood vessels; capillaries are comprised almost entirely of endothelial cells. The angiogenic process involves not only increased endothelial cell proliferation, but also comprises a cascade of additional events, including protease secretion by endothelial cells, degradation of the basement membrane, migration through the surrounding matrix, proliferation, alignment, differentiation into tube-like structures, and synthesis of a new basement membrane. Vasculogenesis involves recruitment and differentiation of mesenchymal cells into angioblasts, which then differentiate into endothelial cells which then form de novo vessels (see, e.g., Folkman et al. Cell 87:1153-5, (1996)).
There is an intense interest in therapeutic protocols that are well-tolerated by the subject, but that are of high potency in effecting stimulation of stem cell and/or progenitor cell recruitment to treat inflammation and affect wound healing. The methods and compositions of the present invention satisfy these and other long felt needs with the following invention.